Modeling responses of macaque and human retinal ganglion cells to natural images using a convolutional neural network.

Linear-nonlinear (LN) cascade models provide a simple way to capture retinal ganglion cell (RGC) responses to artificial stimuli such as white noise, but their ability to model responses to natural images is limited. Recently, convolutional neural network (CNN) models have been shown to produce light response predictions that were substantially more accurate than those of a LN model. However, this modeling approach has not yet been applied to responses of macaque or human RGCs to natural images. Here, we train and test a CNN model on responses to natural images of the four numerically dominant RGC types in the macaque and human retina - ON parasol, OFF parasol, ON midget and OFF midget cells. Compared with the LN model, the CNN model provided substantially more accurate response predictions. Linear reconstructions of the visual stimulus were more accurate for CNN compared to LN model-generated responses, relative to reconstructions obtained from the recorded data. These findings demonstrate the effectiveness of a CNN model in capturing light responses of major RGC types in the macaque and human retinas in natural conditions.

Spike sorting in the presence of stimulation artifacts: a dynamical control systems approach.

Objective. Bi-directional electronic neural interfaces, capable of both electrical recording and stimulation, communicate with the nervous system to permit precise calibration of electrical inputs by capturing the evoked neural responses. However, one significant challenge is that stimulation artifacts often mask the actual neural signals. To address this issue, we introduce a novel approach that employs dynamical control systems to detect and decipher electrically evoked neural activity despite the presence of electrical artifacts.Approach. Our proposed method leverages the unique spatiotemporal patterns of neural activity and electrical artifacts to distinguish and identify individual neural spikes. We designed distinctive dynamical models for both the stimulation artifact and each neuron observed during spontaneous neural activity. We can estimate which neurons were active by analyzing the recorded voltage responses across multiple electrodes post-stimulation. This technique also allows us to exclude signals from electrodes heavily affected by stimulation artifacts, such as the stimulating electrode itself, yet still accurately differentiate between evoked spikes and electrical artifacts.Main results. We applied our method to high-density multi-electrode recordings from the primate retina in anex vivosetup, using a grid of 512 electrodes. Through repeated electrical stimulations at varying amplitudes, we were able to construct activation curves for each neuron. The curves obtained with our method closely resembled those derived from manual spike sorting. Additionally, the stimulation thresholds we estimated strongly agreed with those determined through manual analysis, demonstrating high reliability (R2=0.951for human 1 andR2=0.944for human 2).Significance. Our method can effectively separate evoked neural spikes from stimulation artifacts by exploiting the distinct spatiotemporal propagation patterns captured by a dense, large-scale multi-electrode array. This technique holds promise for future applications in real-time closed-loop stimulation systems and for managing multi-channel stimulation strategies.

Decomposition of retinal ganglion cell electrical images for cell type and functional inference.

Identifying neuronal cell types and their biophysical properties based on their extracellular electrical features is a major challenge for experimental neuroscience and the development of high-resolution brain-machine interfaces. One example is identification of retinal ganglion cell (RGC) types and their visual response properties, which is fundamental for developing future electronic implants that can restore vision. The electrical image (EI) of a RGC, or the mean spatio-temporal voltage footprint of its recorded spikes on a high-density electrode array, contains substantial information about its anatomical, morphological, and functional properties. However, the analysis of these properties is complex because of the high-dimensional nature of the EI. We present a novel optimization-based algorithm to decompose electrical image into a low-dimensional, biophysically-based representation: the temporally-shifted superposition of three learned basis waveforms corresponding to spike waveforms produced in the somatic, dendritic and axonal cellular compartments. Large-scale multi-electrode recordings from the macaque retina were used to test the effectiveness of the decomposition. The decomposition accurately localized the somatic and dendritic compartments of the cell. The imputed dendritic fields of RGCs correctly predicted the location and shape of their visual receptive fields. The inferred waveform amplitudes and shapes accurately identified the four major primate RGC types (ON and OFF midget and parasol cells), a substantial advance. Together, these findings may contribute to more accurate inference of RGC types and their original light responses in the degenerated retina, with possible implications for other electrical imaging applications.

Fixational Eye Movements Enhance the Precision of Visual Information Transmitted by the Primate Retina.

Fixational eye movements alter the number and timing of spikes transmitted from the retina to the brain, but whether these changes enhance or degrade the visual signal is unclear. To quantify this, we developed a Bayesian method for reconstructing natural images from the recorded spikes of hundreds of macaque retinal ganglion cells (RGCs) of the major cell types, combining a likelihood model for RGC light responses with the natural image prior implicitly embedded in an artificial neural network optimized for denoising. The method matched or surpassed the performance of previous reconstruction algorithms, and provided an interpretable framework for characterizing the retinal signal. Reconstructions were improved with artificial stimulus jitter that emulated fixational eye movements, even when the jitter trajectory was inferred from retinal spikes. Reconstructions were degraded by small artificial perturbations of spike times, revealing more precise temporal encoding than suggested by previous studies. Finally, reconstructions were substantially degraded when derived from a model that ignored cell-to-cell interactions, indicating the importance of stimulus-evoked correlations. Thus, fixational eye movements enhance the precision of the retinal representation.

Inferring light responses of primate retinal ganglion cells using intrinsic electrical signatures.

Objective. Retinal implants are designed to stimulate retinal ganglion cells (RGCs) in a way that restores sight to individuals blinded by photoreceptor degeneration. Reproducing high-acuity vision with these devices will likely require inferring the natural light responses of diverse RGC types in the implanted retina, without being able to measure them directly. Here we demonstrate an inference approach that exploits intrinsic electrophysiological features of primate RGCs.Approach.First, ON-parasol and OFF-parasol RGC types were identified using their intrinsic electrical features in large-scale multi-electrode recordings from macaque retina. Then, the electrically inferred somatic location, inferred cell type, and average linear-nonlinear-Poisson model parameters of each cell type were used to infer a light response model for each cell. The accuracy of the cell type classification and of reproducing measured light responses with the model were evaluated.Main results.A cell-type classifier trained on 246 large-scale multi-electrode recordings from 148 retinas achieved 95% mean accuracy on 29 test retinas. In five retinas tested, the inferred models achieved an average correlation with measured firing rates of 0.49 for white noise visual stimuli and 0.50 for natural scenes stimuli, compared to 0.65 and 0.58 respectively for models fitted to recorded light responses (an upper bound). Linear decoding of natural images from predicted RGC activity in one retina showed a mean correlation of 0.55 between decoded and true images, compared to an upper bound of 0.81 using models fitted to light response data.Significance.These results suggest that inference of RGC light response properties from intrinsic features of their electrical activity may be a useful approach for high-fidelity sight restoration. The overall strategy of first inferring cell type from electrical features and then exploiting cell type to help infer natural cell function may also prove broadly useful to neural interfaces.

Inference of Electrical Stimulation Sensitivity from Recorded Activity of Primate Retinal Ganglion Cells.

High-fidelity electronic implants can in principle restore the function of neural circuits by precisely activating neurons via extracellular stimulation. However, direct characterization of the individual electrical sensitivity of a large population of target neurons, to precisely control their activity, can be difficult or impossible. A potential solution is to leverage biophysical principles to infer sensitivity to electrical stimulation from features of spontaneous electrical activity, which can be recorded relatively easily. Here, this approach is developed and its potential value for vision restoration is tested quantitatively using large-scale multielectrode stimulation and recording from retinal ganglion cells (RGCs) of male and female macaque monkeys ex vivo Electrodes recording larger spikes from a given cell exhibited lower stimulation thresholds across cell types, retinas, and eccentricities, with systematic and distinct trends for somas and axons. Thresholds for somatic stimulation increased with distance from the axon initial segment. The dependence of spike probability on injected current was inversely related to threshold, and was substantially steeper for axonal than somatic compartments, which could be identified by their recorded electrical signatures. Dendritic stimulation was largely ineffective for eliciting spikes. These trends were quantitatively reproduced with biophysical simulations. Results from human RGCs were broadly similar. The inference of stimulation sensitivity from recorded electrical features was tested in a data-driven simulation of visual reconstruction, revealing that the approach could significantly improve the function of future high-fidelity retinal implants.SIGNIFICANCE STATEMENT This study demonstrates that individual in situ primate retinal ganglion cells of different types respond to artificially generated, external electrical fields in a systematic manner, in accordance with theoretical predictions, that allows for prediction of electrical stimulus sensitivity from recorded spontaneous activity. It also provides evidence that such an approach could be immensely helpful in the calibration of clinical retinal implants.

High-Fidelity Reproduction of Visual Signals by Electrical Stimulation in the Central Primate Retina.

Electrical stimulation of retinal ganglion cells (RGCs) with electronic implants provides rudimentary artificial vision to people blinded by retinal degeneration. However, current devices stimulate indiscriminately and therefore cannot reproduce the intricate neural code of the retina. Recent work has demonstrated more precise activation of RGCs using focal electrical stimulation with multielectrode arrays in the peripheral macaque retina, but it is unclear how effective this can be in the central retina, which is required for high-resolution vision. This work probes the neural code and effectiveness of focal epiretinal stimulation in the central macaque retina, using large-scale electrical recording and stimulation ex vivo The functional organization, light response properties, and electrical properties of the major RGC types in the central retina were mostly similar to the peripheral retina, with some notable differences in density, kinetics, linearity, spiking statistics, and correlations. The major RGC types could be distinguished by their intrinsic electrical properties. Electrical stimulation targeting parasol cells revealed similar activation thresholds and reduced axon bundle activation in the central retina, but lower stimulation selectivity. Quantitative evaluation of the potential for image reconstruction from electrically evoked parasol cell signals revealed higher overall expected image quality in the central retina. An exploration of inadvertent midget cell activation suggested that it could contribute high spatial frequency noise to the visual signal carried by parasol cells. These results support the possibility of reproducing high-acuity visual signals in the central retina with an epiretinal implant.SIGNIFICANCE STATEMENT Artificial restoration of vision with retinal implants is a major treatment for blindness. However, present-day implants do not provide high-resolution visual perception, in part because they do not reproduce the natural neural code of the retina. Here, we demonstrate the level of visual signal reproduction that is possible with a future implant by examining how accurately responses to electrical stimulation of parasol retinal ganglion cells can convey visual signals. Although the precision of electrical stimulation in the central retina was diminished relative to the peripheral retina, the quality of expected visual signal reconstruction in parasol cells was greater. These findings suggest that visual signals could be restored with high fidelity in the central retina using a future retinal implant.

Large-scale interrogation of retinal cell functions by 1-photon light-sheet microscopy.

Visual processing in the retina depends on the collective activity of large ensembles of neurons organized in different layers. Current techniques for measuring activity of layer-specific neural ensembles rely on expensive pulsed infrared lasers to drive 2-photon activation of calcium-dependent fluorescent reporters. We present a 1-photon light-sheet imaging system that can measure the activity in hundreds of neurons in the ex vivo retina over a large field of view while presenting visual stimuli. This allows for a reliable functional classification of different retinal cell types. We also demonstrate that the system has sufficient resolution to image calcium entry at individual synaptic release sites across the axon terminals of dozens of simultaneously imaged bipolar cells. The simple design, large field of view, and fast image acquisition make this a powerful system for high-throughput and high-resolution measurements of retinal processing at a fraction of the cost of alternative approaches.

Focal electrical stimulation of human retinal ganglion cells for vision restoration.

Objective. Vision restoration with retinal implants is limited by indiscriminate simultaneous activation of many cells and cell types, which is incompatible with reproducing the neural code of the retina. Recent work has shown that primate retinal ganglion cells (RGCs), which transmit visual information to the brain, can be directly electrically activated with single-cell, single-spike, cell-type precision - however, this possibility has never been tested in the human retina. In this study we aim to characterize, for the first time, direct in situ extracellular electrical stimulation of individual human RGCs.Approach. Extracellular electrical stimulation of individual human RGCs was conducted in three human retinas ex vivo using a custom large-scale, multi-electrode array capable of simultaneous recording and stimulation. Measured activation properties were compared directly to extensive results from macaque.Main results. Precise activation was in many cases possible without activating overlying axon bundles, at low stimulation current levels similar to those used in macaque. The major RGC types could be identified and targeted based on their distinctive electrical signatures. The measured electrical activation properties of RGCs, combined with a dynamic stimulation algorithm, was sufficient to produce an evoked visual signal that was nearly optimal given the constraints of the interface.Significance. These results suggest the possibility of high-fidelity vision restoration in humans using bi-directional epiretinal implants.

Individual variability of neural computations in the primate retina.

Variation in the neural code contributes to making each individual unique. We probed neural code variation using ∼100 population recordings from major ganglion cell types in the macaque retina, combined with an interpretable computational representation of individual variability. This representation captured variation and covariation in properties such as nonlinearity, temporal dynamics, and spatial receptive field size and preserved invariances such as asymmetries between On and Off cells. The covariation of response properties in different cell types was associated with the proximity of lamination of their synaptic input. Surprisingly, male retinas exhibited higher firing rates and faster temporal integration than female retinas. Exploiting data from previously recorded retinas enabled efficient characterization of a new macaque retina, and of a human retina. Simulations indicated that combining a large dataset of retinal recordings with behavioral feedback could reveal the neural code in a living human and thus improve vision restoration with retinal implants.

Automatic Identification of Axon Bundle Activation for Epiretinal Prosthesis.

OBJECTIVE: Retinal prostheses must be able to activate cells in a selective way in order to restore high-fidelity vision. However, inadvertent activation of far-away retinal ganglion cells (RGCs) through electrical stimulation of axon bundles can produce irregular and poorly controlled percepts, limiting artificial vision. In this work, we aim to provide an algorithmic solution to the problem of detecting axon bundle activation with a bi-directional epiretinal prostheses. METHODS: The algorithm utilizes electrical recordings to determine the stimulation current amplitudes above which axon bundle activation occurs. Bundle activation is defined as the axonal stimulation of RGCs with unknown soma and receptive field locations, typically beyond the electrode array. The method exploits spatiotemporal characteristics of electrically-evoked spikes to overcome the challenge of detecting small axonal spikes. RESULTS: The algorithm was validated using large-scale, single-electrode and short pulse, ex vivo stimulation and recording experiments in macaque retina, by comparing algorithmically and manually identified bundle activation thresholds. For 88% of the electrodes analyzed, the threshold identified by the algorithm was within ±10% of the manually identified threshold, with a correlation coefficient of 0.95. CONCLUSION: This works presents a simple, accurate and efficient algorithm to detect axon bundle activation in epiretinal prostheses. SIGNIFICANCE: The algorithm could be used in a closed-loop manner by a future epiretinal prosthesis to reduce poorly controlled visual percepts associated with bundle activation. Activation of distant cells via axonal stimulation will likely occur in other types of retinal implants and cortical implants, and the method may therefore be broadly applicable.

Spatially patterned bi-electrode epiretinal stimulation for axon avoidance at cellular resolution.

Objective.Epiretinal prostheses are designed to restore vision to people blinded by photoreceptor degenerative diseases by stimulating surviving retinal ganglion cells (RGCs), which carry visual signals to the brain. However, inadvertent stimulation of RGCs at their axons can result in non-focal visual percepts, limiting the quality of artificial vision. Theoretical work has suggested that axon activation can be avoided with current stimulation designed to minimize the second spatial derivative of the induced extracellular voltage along the axon. However, this approach has not been verified experimentally at the resolution of single cells.Approach.In this work, a custom multi-electrode array (512 electrodes, 10µm diameter, 60µm pitch) was used to stimulate and record RGCs in macaque retinaex vivoat single-cell, single-spike resolution. RGC activation thresholds resulting from bi-electrode stimulation, which consisted of bipolar currents simultaneously delivered through two electrodes straddling an axon, were compared to activation thresholds from traditional single-electrode stimulation.Main results.On average, across three retinal preparations, the bi-electrode stimulation strategy reduced somatic activation thresholds (∼21%) while increasing axonal activation thresholds (∼14%), thus favoring selective somatic activation. Furthermore, individual examples revealed rescued selective activation of somas that was not possible with any individual electrode.Significance.This work suggests that a bi-electrode epiretinal stimulation strategy can reduce inadvertent axonal activation at cellular resolution, for high-fidelity artificial vision.

Reconstruction of natural images from responses of primate retinal ganglion cells.

The visual message conveyed by a retinal ganglion cell (RGC) is often summarized by its spatial receptive field, but in principle also depends on the responses of other RGCs and natural image statistics. This possibility was explored by linear reconstruction of natural images from responses of the four numerically-dominant macaque RGC types. Reconstructions were highly consistent across retinas. The optimal reconstruction filter for each RGC - its visual message - reflected natural image statistics, and resembled the receptive field only when nearby, same-type cells were included. ON and OFF cells conveyed largely independent, complementary representations, and parasol and midget cells conveyed distinct features. Correlated activity and nonlinearities had statistically significant but minor effects on reconstruction. Simulated reconstructions, using linear-nonlinear cascade models of RGC light responses that incorporated measured spatial properties and nonlinearities, produced similar results. Spatiotemporal reconstructions exhibited similar spatial properties, suggesting that the results are relevant for natural vision.

Vision begins in the retina, the layer of tissue that lines the back of the eye. Light-sensitive cells called rods and cones absorb incoming light and convert it into electrical signals. They pass these signals to neurons called retinal ganglion cells (RGCs), which convert them into electrical signals called spikes. Spikes from RGCs then travel along the optic nerve to the brain. They are the only source of visual information that the brain receives. From this information, the brain constructs our entire visual world. The primate retina contains roughly 20 types of RGCs. Each encodes a different visual feature, such as the presence of bright spots of a certain size, or information about texture and movement. But exactly what input each RGC sends to the brain, and how the brain uses this information, is unclear. Brackbill et al. set out to answer these questions by measuring and analyzing the electrical activity in isolated retinas from macaque monkeys. Studying the macaque retina was important because the primate visual system differs from that of other species in several ways. These include the numbers and types of RGCs present in the retina. These primates are also similar to humans in their high-resolution central vision and trichromatic color vision. Using electrode arrays to monitor hundreds of RGCs at the same time, Brackbill et al. recorded the responses of macaque retinas to real-life images of landscapes, objects, animals or people. Based on these recordings, plus existing knowledge about RGC responses, Brackbill et al. then attempted to reconstruct the original images using just the electrical activity recorded. The resulting reconstructions were similar across all retinas tested. Moreover, they showed a striking resemblance to the original images. These results made it possible to comprehend how the light-response properties of each cell represent visual information that can be used by the brain. Understanding how macaque retinas work in natural conditions is critical to decoding how our own retinas process and convey information. A better knowledge of how the brain uses this input to generate images could ultimately make it possible to design artificial retinas to restore vision in patients with certain forms of blindness.

Inference of nonlinear receptive field subunits with spike-triggered clustering.

Responses of sensory neurons are often modeled using a weighted combination of rectified linear subunits. Since these subunits often cannot be measured directly, a flexible method is needed to infer their properties from the responses of downstream neurons. We present a method for maximum likelihood estimation of subunits by soft-clustering spike-triggered stimuli, and demonstrate its effectiveness in visual neurons. For parasol retinal ganglion cells in macaque retina, estimated subunits partitioned the receptive field into compact regions, likely representing aggregated bipolar cell inputs. Joint clustering revealed shared subunits between neighboring cells, producing a parsimonious population model. Closed-loop validation, using stimuli lying in the null space of the linear receptive field, revealed stronger nonlinearities in OFF cells than ON cells. Responses to natural images, jittered to emulate fixational eye movements, were accurately predicted by the subunit model. Finally, the generality of the approach was demonstrated in macaque V1 neurons.

Impact of sodium caseinate, soy lecithin and carrageenan on functionality of oil-in-water emulsions.

Oil-in-water emulsions are the main component of creamers, which are used to cream cold or hot coffee. These emulsions must provide the required lightening power and remain physically stable when introduced into hot acidic coffee solutions. In this study, model oil-in-water emulsions stabilized with mixed emulsifiers of sodium caseinate (0.5%) and soy lecithin (0.5%) were fabricated and their physical properties were examined over a range of pH values (pH 3.5 to 7). These model oil-in-water emulsions had strong lightening power (L* ≈ 87) and good physical stability from pH 5.5 to 7 but were unstable to gravitational separation below pH 5 due to caseinate aggregation around its isoelectric point. Addition of λ-carrageenan (0.05 to 0.175%) to the formulations prior to homogenization effectively improved their pH stability, while addition of κ-carrageenan was ineffective. The significantly higher level of sulfated ester groups in λ-carrageenan may have created a strong electrostatic repulsion between the oil particles, inhibiting their association. Our study suggests that some of the caseinate in coffee creamers can be replaced with plant-based lecithins, but that a plant-based polysaccharide is also needed to ensure their stability when added to hot acidic coffees.

Unusual Physiological Properties of Smooth Monostratified Ganglion Cell Types in Primate Retina.

The functions of the diverse retinal ganglion cell types in primates and the parallel visual pathways they initiate remain poorly understood. Here, unusual physiological and computational properties of the ON and OFF smooth monostratified ganglion cells are explored. Large-scale multi-electrode recordings from 48 macaque retinas revealed that these cells exhibit irregular receptive field structure composed of spatially segregated hotspots, quite different from the classic center-surround model of retinal receptive fields. Surprisingly, visual stimulation of different hotspots in the same cell produced spikes with subtly different spatiotemporal voltage signatures, consistent with a dendritic contribution to hotspot structure. Targeted visual stimulation and computational inference demonstrated strong nonlinear subunit properties associated with each hotspot, supporting a model in which the hotspots apply nonlinearities at a larger spatial scale than bipolar cells. These findings reveal a previously unreported nonlinear mechanism in the output of the primate retina that contributes to signaling spatial information.

Modulation of caseinate-stabilized model oil-in-water emulsions with soy lecithin.

Demands for plant-based food and beverage products have escalated in recent years. However, many commercial coffee creamers are still being made using dairy derivatives such as sodium caseinate. Therefore, there is a need to investigate the replacement of dairy based proteins with plant-based alternatives. This study was carried out to systematically investigate the properties of model O/W emulsions stabilized by either sodium caseinate (0.25 to 1.5%) or soy lecithin (0.5 to 1.5%). The model emulsions were made of 10% medium chain triglyceride (MCT) oil-in-water emulsions at pH 7. All model O/W emulsions exhibited whitish appearances similar to that of commercial creamers and were effective at lightening black coffee, except those containing the lowest emulsifier concentrations i.e., 0.25% caseinate or 0.5% lecithin. The lightness of the model emulsions depended on the type and level of emulsifier used, with soy lecithin-stabilized emulsions having similar lightening power compare to that stabilized by sodium caseinate. No feathering or free oil were observed in the whitened coffees at the highest emulsifier level used. Mixtures of caseinate and lecithin emulsifiers were also used and model O/W emulsions with similar physical properties to that stabilized by sodium caseinate alone were produced. The mixed emulsifier-stabilized model emulsions had similar lightness when added to coffee than those stabilized by the individual emulsifiers, suggesting similar stabilization mechanisms using these emulsifiers alone or in combination.

Epiretinal stimulation with local returns enhances selectivity at cellular resolution.

OBJECTIVE: Epiretinal prostheses are designed to restore vision in people blinded by photoreceptor degenerative diseases, by directly activating retinal ganglion cells (RGCs) using an electrode array implanted on the retina. In present-day clinical devices, current spread from the stimulating electrode to a distant return electrode often results in the activation of many cells, potentially limiting the quality of artificial vision. In the laboratory, epiretinal activation of RGCs with cellular resolution has been demonstrated with small electrodes, but distant returns may still cause undesirable current spread. Here, the ability of local return stimulation to improve the selective activation of RGCs at cellular resolution was evaluated. APPROACH: A custom multi-electrode array (512 electrodes, 10 µm diameter, 60 µm pitch) was used to simultaneously stimulate and record from RGCs in isolated primate retina. Stimulation near the RGC soma with a single electrode and a distant return was compared to stimulation in which the return was provided by six neighboring electrodes. MAIN RESULTS: Local return stimulation enhanced the capability to activate cells near the central electrode (<30 µm) while avoiding cells farther away (>30 µm). This resulted in an improved ability to selectively activate ON and OFF cells, including cells encoding immediately adjacent regions in the visual field. SIGNIFICANCE: These results suggest that a device that restricts the electric field through local returns could optimize activation of neurons at cellular resolution, improving the quality of artificial vision.

Stereotyped Synaptic Connectivity Is Restored during Circuit Repair in the Adult Mammalian Retina.

Proper function of the central nervous system (CNS) depends on the specificity of synaptic connections between cells of various types. Cellular and molecular mechanisms responsible for the establishment and refinement of these connections during development are the subject of an active area of research [1-6]. However, it is unknown if the adult mammalian CNS can form new type-selective synapses following neural injury or disease. Here, we assess whether selective synaptic connections can be reestablished after circuit disruption in the adult mammalian retina. The stereotyped circuitry at the first synapse in the retina, as well as the relatively short distances new neurites must travel compared to other areas of the CNS, make the retina well suited to probing for synaptic specificity during circuit reassembly. Selective connections between short-wavelength sensitive cone photoreceptors (S-cones) and S-cone bipolar cells provides the foundation of the primordial blue-yellow vision, common to all mammals [7-18]. We take advantage of the ground squirrel retina, which has a one-to-one S-cone-to-S-cone-bipolar-cell connection, to test if this connectivity can be reestablished following local photoreceptor loss [8, 19]. We find that after in vivo selective photoreceptor ablation, deafferented S-cone bipolar cells expand their dendritic trees. The new dendrites randomly explore the proper synaptic layer, bypass medium-wavelength sensitive cone photoreceptors (M-cones), and selectively synapse with S-cones. However, non-connected dendrites are not pruned back to resemble unperturbed S-cone bipolar cells. We show, for the first time, that circuit repair in the adult mammalian retina can recreate stereotypic selective wiring.

Temporal structure in spiking patterns of ganglion cells defines perceptual thresholds in rodents with subretinal prosthesis.

Subretinal prostheses are designed to restore sight in patients blinded by retinal degeneration using electrical stimulation of the inner retinal neurons. To relate retinal output to perception, we studied behavioral thresholds in blind rats with photovoltaic subretinal prostheses stimulated by full-field pulsed illumination at 20 Hz, and measured retinal ganglion cell (RGC) responses to similar stimuli ex-vivo. Behaviorally, rats exhibited startling response to changes in brightness, with an average contrast threshold of 12%, which could not be explained by changes in the average RGC spiking rate. However, RGCs exhibited millisecond-scale variations in spike timing, even when the average rate did not change significantly. At 12% temporal contrast, changes in firing patterns of prosthetic response were as significant as with 2.3% contrast steps in visible light stimulation of healthy retinas. This suggests that millisecond-scale changes in spiking patterns define perceptual thresholds of prosthetic vision. Response to the last pulse in the stimulation burst lasted longer than the steady-state response during the burst. This may be interpreted as an excitatory OFF response to prosthetic stimulation, and can explain behavioral response to decrease in illumination. Contrast enhancement of images prior to delivery to subretinal prosthesis can partially compensate for reduced contrast sensitivity of prosthetic vision.